Novel Genetic and Phenotypic Expansion in Ameliorated PUF60 -Related Disorders

• Published in: International journal of molecular sciences Vol. 25; no. 4; p. 2053
• Main Authors: Baum, Emily, Huang, Wenming, Vincent-Delorme, Catherine, Brunelle, Perrine, Antebi, Adam, Dafsari, Hormos Salimi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08-02-2024; MDPI
• Series: International Journal of Molecular Sciences
• Subjects: Age; Behavior; Cognitive development; Coloboma; Congenital diseases; Convulsions & seizures; Ear diseases; Electroencephalography; Epilepsy; Failure to thrive; Females; Gastroesophageal reflux; Hearing aids; Hearing loss; Humans; immunological disorders; Infections; Life Sciences; Magnetic resonance imaging; Microcephaly; Mutation, Missense; Myopia; neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Patients; Phenotype; Pneumonia; Pregnancy; PUF60; RNA Splicing Factors - genetics; Skin; Speech; Verheij syndrome; immunological disorders; PUF60; neurodevelopmental disorders; Verheij syndrome; Neurodevelopmental disorders; Immunological disorders
• ISSN: 1422-0067; 1661-6596; 1422-0067; 1661-6596
• DOI: 10.3390/ijms25042053

Heterozygous variants in the Poly(U) Binding Splicing Factor 60kDa gene (
) have been associated with Verheij syndrome, which has the key features of coloboma, short stature, skeletal abnormalities, developmental delay, palatal abnormalities, and congenital heart and kidney defects. Here, we report five novel patients from unrelated families with
-related disorders exhibiting novel genetic and clinical findings with three truncating variants, one splice-site variant with likely reduced protein expression, and one missense variant. Protein modeling of the patient's missense variant in the PUF60 AlphaFold structure revealed a loss of polar bonds to the surrounding residues. Neurodevelopmental disorders were present in all patients, with variability in speech, motor, cognitive, social-emotional and behavioral features. Novel phenotypic expansions included movement disorders as well as immunological findings with recurrent respiratory, urinary and ear infections, atopic diseases, and skin abnormalities. We discuss the role of PUF60 in immunity with and without infection based on recent organismic and cellular studies. As our five patients showed less-severe phenotypes than classical Verheij syndrome, particularly with the absence of key features such as coloboma or palatal abnormalities, we propose a reclassification as
-related neurodevelopmental disorders with multi-system involvement. These findings will aid in the genetic counseling of patients and families.